Controlled Release Formulations

ABSTRACT

Controlled release oral dosage formulations containing one or more active agent, and methods of use thereof, are provided for the once-a-day treatment. The formulation can be in the form of a trilayer tablet containing a core or central layer and one or more barrier layers. The core may contain one or more enteric materials or polymeric materials which modulates the release of the active agent.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.60/824,043, filed on Aug. 30, 2006 and U.S. Provisional Application No.60/824,054, filed on Aug. 30, 2006.

FIELD OF THE INVENTION

This invention is generally in the field of controlled or modifiedrelease formulations of pharmaceutically active agents.

BACKGROUND OF THE INVENTION

A controlled release formulation is a pharmaceutical composition capableof releasing a drug at a pre-determined rate and/or at a pre-determinedtime after administration to maintain a desirable pharmacologicalactivity for some desirable period of time. Such preparations provide asupply of a drug to the body during a predetermined period of time or ata predetermined absorption site and thus maintain drug levels in atherapeutic range for longer periods of time than conventional, e.g.immediate release formulations.

Dosage forms comprising a core containing a drug dispersed inrelease-controlling materials are a popular means of producingcontrolled release formulations. Materials most commonly employed forthis purpose are hydrophilic materials, e.g. hydrophilic polymers thatswell and gel upon contact with a physiological medium. When a dosageform is exposed to a physiological medium, the periphery will begin tohydrate and form a gel matrix. As the medium continues to penetrate thedosage form the thickness of the gel matrix increases. Drug releaseoccurs by diffusion through the matrix and/or by erosion of the matrix.A variety of desirable release profiles can be produced by carefullyselecting the hydrophilic material and the dimensions and geometry ofthe dosage form compositions. However, over time, as the thickness ofthe gel matrix increases, the drug concentration in the dosage formdecreases, the surface area of the dosage form decreases and as a resultthe rate of release decreases.

For many active agents, the rate or extent of absorption is not linearas the agent passes through the GI tract. Many active agents haveso-called absorption windows. An absorption window is a term given to anarea or region of the GI tract where a drug is absorbed more efficientlyor at a higher rate compared with other regions of the GI tract. Someactive agents are more prone to degradation or metabolism in certainregions of the GI tract than others. As such, it would be beneficial ifa controlled release dosage form could deliver the drug almostexclusively to a particular absorption window for a given active agent,or preferentially avoid or reduce the rate of release in areas of the GItract where degradation or metabolism of an active agent is high.Further, the ability to deliver an active agent to the absorption windowmay increase efficacy of the drug substances and/or diminish oreliminate adverse side effects.

There exists a need to provide a controlled release dosage form that,upon administration, releases an active agent initially at a slow ratebut which increases over time, in order to release a drug from thedosage form mainly to the lower region of the GI tract. In particular,there exists a need to provide a dosage form providing for slower drugrelease rates at pH levels below about 5.5 and increased rate of releaseat higher pH levels.

It is therefore an object of the invention to provide controlled releaseformulations which delay release of one or more active agents until theformulation reaches the absorption window, and methods of making andusing thereof.

It is an object of the invention to provide a controlled release dosageform that, upon administration, releases an active agent initially at aslow rate and which rate increases over time, in order to release a drugfrom the dosage form mainly to the lower region of the GI tract.

SUMMARY OF THE INVENTION

Controlled release formulations for the delivery of an active agent, andmethods of making and using thereof, are described herein. In oneembodiment, the formulation contains a core containing an active agentand an enteric material, optionally a hydrophilic material and,optionally one or more barrier layers. The formulation can beadministered in any solid oral dosage form such as a tablet or caplet.In one embodiment, the controlled release formulation is a tabletcontaining a core containing a dihydropyridine calcium channel blocker,such as nisoldipine, and an enteric material, and at least one barrierlayer above or below the central layer which contains one or moreerodible, swellable and/or gellable polymeric materials. Theconcentration of the enteric material in the core is from about 0.1% toabout 20% by weight, preferably about 1 to 15%, more preferably about 5to 10% by weight of the composition. The concentration of the one ormore polymers in the barrier layer(s) is from about 5% to about 90% byweight of the barrier layer, preferably from about 50% to about 90% byweight of the barrier. In a preferred embodiment, the tablet is atrilayer tablet which contains a core, and two barrier layers, one abovethe core and one below. The barrier layers may be the same or differentin composition and thickness. The core and/or barrier layers may containone or more pharmaceutically acceptable additives, excipients, orcarriers.

The core may contain one or more polymeric materials that modulate (i.e.slow and/or accelerate) the release of the active agent. Theconcentration of the polymeric material is from about 1% to about 95% byweight. The central layer and/or the barrier layers may also contain oneor adjuvants, which, in combination with the polymeric materials,further modulate release of the active agent. The concentration of theadjuvant(s) is from about 1% to about 25% by weight of the compositions,preferably from about 5% to about 15% by weight of the composition.

The formulation may be coated with one or more modified releasecoatings, which further modulate the release of the active agent fromthe core. Suitable coatings include immediate release coatings, tastemask coatings, enteric coatings, sustained or extended release coatings,and delayed release coatings. The dosage forms may also be coated foraesthetic reasons such as to impart a color to the dosage form or toapply a surface finish to the dosage form. The dosage form, uponadministration to a subject, releases the active agent with an ascendingrelease rate in response to the changes in pH as the dosage formulationdescends the GI tract.

DETAILED DESCRIPTION OF THE INVENTION I. DEFINITIONS

As used herein, the term “enteric material” refers to a material that istypically employed in enteric coatings. Enteric materials arepractically insoluble at acidic pH levels found in the stomach, but areincreasingly soluble at higher pH levels found in the intestinal tract.

“Taste masking coating”, as used herein, refers to a pH dependentcoating that is insoluble in the mouth but dissolves in the acidic pH ofthe stomach.

“Extended release coating”, as used herein, refers to a pH independentsubstance that will act as a barrier to control the diffusion of thedrug from its core complex into the gastrointestinal fluids.

“Delayed release coating”, as used herein, refers to a pH dependentcoating that is insoluble in the acidic pH of the stomach and the pHwithin the mid to the upper small intestine, but dissolves within thelower small intestine or upper large intestine.

“C_(max)”, as used herein, refers to the peak concentration in bloodplasma. Unless otherwise stated, C_(max) refers to the peakconcentration of the calcium channel blocker in blood plasma.

“T_(max)”, as used herein, refers to the time to peak concentration inblood plasma. Unless otherwise stated, T_(max) refers to the time topeak concentration of the calcium channel blocker in blood plasma.

“λ_(z)”, as used herein, refers to the elimination rate constant.

“T_(1/2), as used herein, refers to the terminal half-life.

“AUC_(last)”, as used herein, refers to the area under theconcentration-time curve from time-zero to the time of the lastquantifiable concentration.

“AUC_(inf)”, as used herein, refers to the area under the plasmaconcentration time curve from time-zero extrapolated to infinity.

“Bioavailability”, as used herein, refers to the rate and of uptake theactive ingredient or active agent absorbed from a drug product.

“Bioequivalence”, as used herein, refers to the equivalent release ofthe same drug substance from two or more drug products or formulations.This leads to an equivalent rate and extent of absorption from theseformulations.

As used herein, an “analog” of a chemical compound is a compound that,by way of example, resembles another in structure but is not necessarilyan isomer (e.g., 5-fluorouracil is an analog of thymine).

As used herein, a “derivative” of a compound refers to a chemicalcompound that may be produced from another compound of similar structurein one or more steps. Derivatives generally involve the addition and/ormodification of one or more functional groups on the parent compound.

As used herein, “controlled release elements” refers to materials thatmodulate release of the active agent from the formulation. Thecontrolled release elements may be located in the core and/or thebarrier layer(s). The controlled release elements may be organic orinorganic, naturally occurring or synthetic, materials including, butnot limited to, polymeric materials, triglycerides, derivatives oftriglycerides, fatty acids and salts of fatty acids, talc, small organicmolecules and salts thereof, talc, boric acid, and colloidal silica.

As used herein, “coat-core nisoldipine 40 mg tablet” for purposes ofcomparison of pharmacokinetics and dosage refers to the version of thedrug marketed as SULAR®, containing 8 mg of nisoldipine in the core and32 mg of nisoldipine in the coat.

II. COMPOSITIONS

A. Core

i. Active Agents

The core or central layer contains one or more active agents selectedfrom the group including, but not limited to, hypnotics, sedatives,tranquilizers, anti-convulsants, muscle relaxants, analgesics,anti-inflammatory, anesthetics, anti-spasmodics, anti-ulcer-agents,anti-parasitics, anti-microbials, anti-fungal, cardiovascular agents,diuretics, cytostatics, anti-neoplastic agents, anti-viral agents,anti-glaucoma agents, anti-depressants, sympathomimetics,hypoglycaemics, diagnostic agents, anti-cough, physic energizers,anti-parkinson agents, local anesthetics, muscle contractants,anti-malarials, hormonal agents, contraceptives, anorexic,anti-arthritic, anti-diabetic, anti-hypertensive, anti-pyretic,anti-cholinergic, bronchodilator, central nervous system, inotropic,vasodilator, vasoconstrictor, decongestant, hematinic, electrolytesupplement, germicidal, parasympathetolytic, parasymphatethomimetic,antiemetic, psychostimulant, vitamin, beta-blockers, H-2 blocker, beta-2agonist, counterirritants, coagulating modifying agents, stimulants,anti-hormones, drug-antagonists, lipid-regulating agents, uricosurics,cardiac glycosides, ergot and derivatives thereof, expectorants, musclerelaxants, anti-histamines, purgatives, contrast materials,radiopharmaceuticals, imaging agents, anti-allergic agents, andcombinations thereof.

Suitable active agents include, but are not limited to, codeine,ethylmorphine, dextromethorphan, noscapine, pentoxiverine,acetylcysteine, bromhexine, epinephrine, isoprenaline, orciprenaline,ephedrine, fenoterol, rimiterol, ipratropium, cholinetheophyllinate,proxiphylline, bechlomethasone, budesonide, deslanoside, digoxine,digitoxin, disopyramide, proscillaridin, chinidine, procainamide,mexiletin, flecainide, alprenolol, proproanolol, nadolol, pindolol,oxprenolol, labetalol, timolol, atenolol, pentaeritrityltetranitrate,isosorbiddinitrate, isosorbidmononitrate, niphedipin, phenylamnine,verapamil, cyclandelar, nicotinylalcholhol, inositolnicotinate,alprostatdil, etilephrine, prenalterol, dobutamine, dopamine,dihydroergotamine, guanetidine, betanidine, methyldopa, reserpine,guanfacine, trimethaphan, hydralazine, dihydralazine, prazosine,diazoxid, captopril, nifedipine, nisoldipine, enalapril, nitroprusside,bendroflumethiaziede, hydrochlorthiazide, metychlothiazide,polythiazide, chlorthalidon, cinetazon, clopamide, mefruside,metholazone, bumetanide, ethacrynacide, spironolactone, amiloride,chlofibrate, nicotinic acid, nicheritrol, brompheniramine, cinnarizine,dexchlorpheniramine, clemastine, antazoline, cyproheptadine,promethazine, cimetidine, ranitidine, sucralfat, papaverine, moxaverine.atropin, butylscopolamin, emepron, glucopyrron, hyoscyamine, mepensolar,methylscopolamine, oxiphencyclimine, probanteline, terodilin,sennaglycosides, sagradaextract, dantron, bisachodyl, sodiumpicosulfat,etulos, diphenolxylate, loperamide, salazosulfapyridine, pyrvin,mebendazol, dimeticon, ferrofuimarate, ferrosuccinate,ferritetrasemisodium, cyanochobalamine, folic acid heparin, heparinco-factor, diculmarole, warfarin, streptokinase, urokinase, factor VIII,factor IX, vitamin K, thiotepa, busulfan, chlorambucil, cyclophosphamid,melfalan, carmustin, mercaptopurinl, thioguanin, azathioprin, cytarabin,vinblastin, vinchristin, vindesin, procarbazine, dacarbazine, lomustin,estramustin, teniposide, etoposide, cisplatin, amsaclirin,aminogluthetimid, phosphestrol, medroxiprogresterone,hydroxiprogresterone, megesterol, noretisteron, tamoxiphen, ciclosporin,sulfisomidine, bensylpenicillin, phenoxymethylpenicillin, dicloxacillin,cloxacillin, flucloxacillin, ampicillin, amoxicillin, pivampicillin,bacampicillin, piperacillin, mezlocillin, mecillinam, pivmecillinam,cephalotin, cephalexin, cephradin, cephadroxil, cephaclor, cefuroxim,cefotaxim, ceftazidim, cefoxitin, aztreonaam, imipenem, cilastatin,tetracycline, lymecycline, demeclocycline, metacycline, oxitetracycline,doxycycline, chloramphenicol, spiramycin, fusidic acid, lincomycin,clindamycin, spectinomycin, rifampicin, amphotericin B, griseofulvin,nystatin, vancomycin, metronidazole, tinidazole, trimethoprim,norfloxacin, salazosulfapyridin, aminosalyl, isoniazid, etambutol,nitrofirantoin, nalidixic acid, metenamine, chloroquin,hydroxichloroquin, tinidazol, ketokonazol, acyclovir, interferonidoxuridin, retinol, tiamin, dexpantenol, pyridoxin, folic acid,ascorbic acid, tokoferol, phytominadion, phenfluramin, corticotropin,tetracosactid, tyrotropin, somatotropin, somatrem, vasopressin,Iypressin, desmopressin, oxytocin, chloriongonadotropin, cortison,hydrocortison, fludrocortison, prednison, prednisolon, fluoximesteron,mesterolon, nandrolon, stanozolol, oximetolon, cyproteron, levotyroxin,liotyronin, propylthiouracil, carbimazol, tiamazol, dihydrotachysterol,alfacalcidol, calcitirol, insulin, tolbutamid, chlorpropamid, tolazamid,glipizid, glibenclamid, phenobarbital, methyprylon, pyrityldion,meprobamat, chlordiazepoxid, diazepam, nitrazepam, oxazepam,dikaliumchlorazepat, lorazepam, flunitrazepam, alprazolam, midazolam,hydroxizin, chlomethiazol, propionmazine, alimemazine, chlorpromazine,levomepromazine, acetophenazine, fluphenazine, perphenazine,prochlorperazine, trifluoperazine, dixyrazine, thioridazine, periciazin,chloprothixene, zuclopentizol, flupentizol, thithixen, haloperidol,trimipramin, opipramol, chlomipramini, desipramin, lofepramin,amitriptylin, nortriptylin, protriptylin, maptrotilin, coffein,cinnarizine, cyclizine, dimenhydinate, meclozine, prometazine,thiethylperazine, metoclopramide, scopolamine, phenobarbital,phenytoine, ethosuximide, primidone, carbamazepine, chlonazepam,orphenadrine, atropine, bensatropine, biperiden, metixene, procylidine,levodopa, bromocriptin, amantadine, ambenon, pyridostigmine,synstigmine, disulfiram, morphine, codeine, pentazocine, buprenorphine,pethidine, phenoperidine fentanyt, methadone, piritramide,dextropropoxyphene, ketobemidone, acetylsalicylic acid, phenazone,phenylbutazone, azapropazone, piroxicam, ergotamine, dihydroergotamine,cyproheptadine, pizitifen, flumedroxon, allopurinol, probenecid,sodiummaurothiomalate, auronofin, penicillamine, estradiol,estradiolvalerianate, estriol, ethinylestradiol, dihydrogesteron,lynestrenol, medroxiprogresterone, noretisterone, cyclophenile,clomiphene, levonorgestrel, mestranol, ornidazol, tinidazol, ekonazol,chlotrimazol, natamycine, miconazole, sulbentin, methylergotamine,dinoprost, dinoproston, gemeprost, bromocriptine, phenylpropanolamine,sodiumchromoglicate, azetazolamide, dichlophenamide, betacarotene,naloxone, calciumfolinate, in particular clonidine, theophylline,dipyradamol, lydrochlorthiazide, scopolamine, indomethacine, furosemide,potassium chloride, morphine, ibuprofen, salbutamol, terbutalin, andcombinations thereof.

The active agent(s) can be chiral or achiral. Chiral molecules can existas a single enantiomer, a mixture of enantiomers or diastereomers or aracemic mixture. As used herein, the term “stereoisomers” refers tocompounds made up of the same atoms having the same bond order buthaving different three-dimensional arrangements of atoms which are notinterchangeable. The three-dimensional structures are calledconfigurations. As used herein, the term “enantiomers” refers to twostereoisomers which are non-superimposable mirror images of one another.As used herein, the term “optical isomer” is equivalent to the term“enantiomer”. As used herein the term “diastereomer” refers to twostereoisomers which are not mirror images and are not superimposable.The terms “racemate”, “racemic mixture” or “racemic modification” referto a mixture of equal parts of enantiomers. The term “chiral center”refers to a carbon atom to which four different groups are attached.Choice of the appropriate chiral column, eluent, and conditionsnecessary to effect separation of the pair of enantiomers is well knownto one of ordinary skill in the art using standard techniques (see e.g.Jacques, J. et al., “Enantiomers, Racemates, and Resolutions”, JohnWiley and Sons, Inc. 1981).

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the compounds listed above, wherein the parent compound is modifiedby making the acid or base addition salt thereof. Example ofpharmaceutically acceptable salts include but are not limited to mineralor organic acid salts of basic residues such as amines; and alkali ororganic salts of acidic residues such as carboxylic acids. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. Suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric acids; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,tolunesulfonic, naphthalenesulfonic, methanesulfonic, ethane disulfonic,oxalic, and isethionic salts.

The pharmaceutically acceptable salts of the compounds can besynthesized from the parent compound, which contains a basic or acidicmoiety, by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like diethyl ether, ethyl acetate, ethanol, isopropanol, oracetonitrile are preferred. Lists of suitable salts are found inRemington's Pharmaceutical Sciences, 20th ed., Lippincott Williams &Wilkins, Baltimore, Md., 2000, p. 704; and “Handbook of PharmaceuticalSalts: Properties, Selection, and Use,” P. Heinrich Stahl and Camille G.Wermuth, Eds., Wiley-VCH, Weinheim, 2002.

As generally used herein “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problems or complicationscommensurate with a reasonable benefit/risk ratio.

The amount of active agent(s) employed in a dosage form will depend onthe active agent(s) to be employed and the nature and severity of thecondition to be treated. The concentration of the active agent isgenerally from about 0.1% to about 90% by weight of the tablet,preferably from about 0.5% to about 20% by weight of the tablet, morepreferably from about 1% to about 10% by weight of the tablet.Alternatively, the concentration of the active agent is generally fromabout 0.1% to about 90% by weight of the core, preferably from about0.5% to about 20% of the core, more preferably from about 1% to about10% of the core.

In the preferred embodiment, the active agent is a dihydropyridinecalcium channel blocker, such as nisoldipine or a derivative, analogue,or polymorph thereof. Nisoldipine is a yellow crystalline substance,which is practically insoluble in water, but soluble in ethanol.Derivatives of nisoldipine, such as m-nisoldipine, are described in Wanget al., J. Chrom. B, 835, 71-76 (2006)).

B. Controlled Release Elements

1. Enteric Material

The core or central layer contains an enteric material to delay therelease of the one or more active agents until the formulation reachesthe absorption window. Suitable enteric materials include, but are notlimited to, cellulose polymers, such as cellulose acetate phthalate,hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate andhydroxypropyl methylcellulose acetate succinate; polyvinyl acetatephthalate, acrylic acid polymers and copolymers, and methacrylic resinsthat are commercially available under the trade name Eudragit® (RoluPharma), such aspoly(ethylacrylate-methylmethaerylate-triethylammonioethyl-metharylatechloride) (Eudragit® RS and Eudragit® RL) andpoly(ethylacrylate-methylmethacrylate) (Eudragit® NE); alginates,alkali-soluble acrylic resins, hydroxypropyl methylcellulose phthalate,methacrylate-methacrylic acid co-polymers, polyvinyl acetate phthalate,styrol maleic acid copolymers, and the like, and combinations thereof.In one embodiment, the enteric material is cellulose acetate phthalate.The concentration of the enteric material is from about 0.1% to about20% by weight, preferably about 1 to 15%, more preferably about 5 to 10%by weight of the composition.

2. Hydrophilic Materials

The core may also contain one or more hydrophilic materials thatmodulate (i.e. slow and/or accelerate) the release of the activeagent(s). The hydrophilic material may be any of the materials known inthe art used in dosage forms as matrix-forming release-controllingagents. Examples of such materials include, but are not limited to,methyl cellulose, carboxymethyl-cellulose sodium, crosslinkedcarboxymethylcellulose sodium, crosslinked hydroxypropylcellulose,hydroxypropylmethylcellulose, carboxymethyl starch, polymethacrylate,polyvinylpyrrolidone, polyvinyl alcohols, polyethylene glycols,potassium methacrylate-divinyl benzene copolymer,carboxymethylcellulose, alginates, albumin, gelatine, crosslinkedpolyvinylpyrrolidone, soluble starch and derivatives thereof,polyesters, polyanhydrides, polymethylvinylether/anhydride copolymers,glucan, scleroglucan, mannan, betacyclodextrins and cyclodextrinderivatives containing linear and/or branched polymeric chains andmixtures thereof The various types of the materials mentioned above arecommercially and cab be characterized by differences in chemico-physicalcharacteristics such as solubility and gel formation. For example, theerodibility, gelation, and ability to swell of hydroxypropylmethylcellulose can vary based on the molecular weight of the polymer and thedegree of substitution. Therefore, one skilled in the art would be ableto select from among polymers with the same molecular structure butdiffering in the molecular weight and/or viscosity, based on the desiredrelease profile of the active agent. In one embodiment, the corecontains Methocel® K4M, a hydroxypropyl metlhycellulose having a methoxycontent of 19-24%, a hydroxypropoxyl content of 7-12%, and an apparentviscosity, as measured on a 2% aqueous solution by rotation, of2308-3755 mPa (Colorcon, West Point, Pa.). In another embodiment, thecore contains Methocel® K100LV, a hydroxypropyl methycellulose having amethoxy content of 19-24%, a hydroxypropoxyl content of 7-12%, and anapparent viscosity, as measured on 2% aqueous solution by rotation, of78-117 mPa (Colorcon, West Point, Pa.).

The concentration of the hydrophilic material is from about 1% to about90% by weight of the composition, preferably from about 10% to about 50%by weight, more preferably from about 10 to 45% by weight of thecomposition.

Upon contact with a physiological medium, the core containing the activeagent, the enteric material and the hydrophilic material form a gelmatrix. The gel matrix must have sufficient strength such that itmaintains its structural integrity throughout the period of drugrelease. At low pH levels in the stomach, the enteric material remainsinsoluble. However, as the dosage form descends further down the GItract, the enteric material is increasingly solubilised, therebyincreasingly creating pores and channels in the matrix through whichdrug can diffuse at increasing rates. The enteric materials are notswellable and/or gellable in aqueous media, and thus, do not contributemechanical strength of the gel matrix. It is important that thedesirable effect the enteric material has on the release rate is notoffset by the unintended effect of prematurely destroying the structuralintegrity of the gel matrix. In order to ensure that a desired releaserate can be obtained reproducibly, it is preferred that the entericmaterial is used in low amounts relative to the amount of hydrophilicmaterial employed. Most preferably the ratio of hydrophilic material tothe enteric material is about 1.5:1 to about 10:1, more particularlyabout 1.9:1 to about 5:1.

C. Barrier Layer(s)

The barrier layer(s) serve to prevent, for a predetermined amount oftime, the release of the active agent contained in the central layer orcore. The tablet can contain one or more barrier layers. When twobarrier layers are present, the barriers layers may have the samecomposition or different compositions and/or the same thickness ordifferent thicknesses.

In one embodiment, the barrier layer(s) contain(s) one or moreswellable, erodible and/or gellable polymers. In a preferred embodimentthe swellable, erodible, and/or gellable polymer ishydroxypropylmethylcellulose. The weight average molecular weight of thehydroxypropylmethylcellulose is from about 1000 to about 4,000,000, morepreferably from about 2000 to about 2,000,000.

In one embodiment, the barrier layer(s) contain Methocel® E5, ahydroxypropyl methycellulose having a methoxy content of 28-30%, ahydroxypropoxyl content of 7-12%, and an apparent viscosity, as measuredby rotation, of 4.2-6.1 mPa (Colorcon, West Point, Pa.). In anotherembodiment, the barrier layer(s) contain Methocel® E50, a hydroxypropylmethycellulose having a methoxy content of 28-30%, a hydroxypropoxylcontent of 7-12%, and an apparent viscosity, as measured by rotation, of39-59 mPa (Colorcon, West Point, Pa.). In a preferred embodiment, onebarrier layer contains Methocel® ES and the second barrier layercontains Methocel® E50.

Other suitable polymers include, but are not limited to, carboxyvinylpolymers; polyvinylalcohols; glucans, scleroglucans; mannans; xantans;alginic acid and its derivatives; polyanhydrides; polyaminoacids;methylvinylethers/maleic anhydride copolymers; carboxymethylcelluloseand its derivatives; ethylcellulose; methylcellulose; and othercellulosic polymers.

The polymers are present in an amount from about 5% to about 90% byweight of the barrier layer, preferably from about 25% to about 75% byweight of the barrier layer.

D. Other Release-Modifying Agents

The core layer and/or the barrier layers may also contain one or moreadjuvants, which in combination with the polymeric materials allows forfurther modulation of the release of the active agent based on thedesired release profile of the active agent. Suitable adjuvants include,but are not limited to, glyceryl monostearate, triglyceride derivatives,semi-synthetic glycerides, hydrogenated castor oil, glycerylpalmitostearate, cetyl alcohol, polyvinylpyrrolidone, glycerol,ethylcellulose, methylcellulose, sodium carboxymethylcellulose, othernatural or synthetic substances well known to those skilled in the art,and combinations thereof. Other suitable adjuvants include, but are notlimited to, magnesium stearate, stearic acid, talc, sodium benzoate,boric acid, polyoxyethylenglycols and colloidal silica. Theconcentration of the adjuvant(s) is from about 1% to about 25% by weightof the compositions, preferably from about 5% to about 15% by weight ofthe composition.

E. Additives, Excipients and Carriers

Formulations may be prepared using a pharmaceutically acceptable carriercomposed of materials that are considered safe and effective and may beadministered to an individual without causing undesirable biologicalside effects or unwanted interactions. The carrier is all componentspresent in the pharmaceutical formulation other than the activeagent(s). As generally used herein “carrier” includes, but is notlimited to, plasticizers, diluents, binders, lubricants, surfactants, pHmodifying agents, anti-adherents, disintegrators, fillers, pigments,colorants, stabilizing agents, flavoring agents, glidants, andcombinations thereof.

Suitable plasticizers include, but are not limited to, hydrogenatedcastor oil, cetyl alcohol, cetostearyl alcohol, fatty acids, glyceridesand triglycerides and derivatives thereof, and polyoxyethylenglycols andderivatives thereof.

Diluents, also referred to as “fillers,” are typically necessary toincrease the bulk of a solid dosage form so that a practical size isprovided for compression of tablets or formation of beads and granules.Suitable diluents include, but are not limited to, dicalcium phosphatedihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol,cellulose, microcrystalline cellulose, kaolin, sodium chloride, drystarch, hydrolyzed starches, pregelatinized starch, silicone dioxide,titanium oxide, magnesium aluminum silicate and powdered sugar. Theamount of active substance released in the first administration phasemay be programmed regulating the exposed surface and the componentsconstituting the layer (a) matrix, all obviously depending on to thesame active principle solubility.

Binders are used to impart cohesive qualities to a solid dosageformulation, and thus ensure that a tablet or bead or granule remainsintact after the formation of the dosage forms. Suitable bindermaterials include, but are not limited to, starch, pregelatinizedstarch, gelatin, sugars (including sucrose, glucose, dextrose, lactoseand sorbitol), polyethylene glycol, waxes, natural and synthetic gumssuch as acacia, tragacanth, sodium alginate, cellulose, includinghydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose,and veegum, and synthetic polymers such as acrylic acid and methacrylicacid copolymers, methacrylic acid copolymers, methyl methacrylatecopolymers, aminoalkyl methacrylate copolymers, polyacrylicacid/polymethacrylic acid and polyvinylpyrrolidone.

Lubricants are used to facilitate tablet manufacture. Examples ofsuitable lubricants include, but are not limited to, magnesium stearate,calcium stearate, stearic acid, glycerol behenate, polyethylene glycol,talc, and mineral oil.

Disintegrants are used to facilitate dosage form disintegration or“breakup” after administration, and generally include, but are notlimited to, starch, sodium starch glycolate, sodium carboxymethylstarch, sodium carboxymethylcellulose, hydroxypropyl cellulose,pregelatinized starch, clays, cellulose, alginine, gums or cross linkedpolymers, such as cross-linked PVP (Polyplasdone XL from GAF ChemicalCorp).

Stabilizers are used to inhibit or retard drug decomposition reactionswhich include, by way of example, oxidative reactions.

Surfactants may be anionic, cationic, amphoteric or nonionic surfaceactive agents. Suitable anionic surfactants include, but are not limitedto, those containing carboxylate, sulfonate and sulfate ions. Examplesof anionic surfactants include sodium, potassium, ammonium of long chainalkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzenesulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzenesulfonate; dialkyl sodium sulfosuccinates, such as sodiumbis-(2-ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodiumlauryl sulfate. Cationic surfactants include, but are not limited to,quaternary ammonium compounds such as benzalkonium chloride,benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzylammonium chloride, polyoxyethylene and coconut amine. Examples ofnonionic surfactants include ethylene glycol monostearate, propyleneglycol myristate, glyceryl monostearate, glyceryl stearate,polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG-150laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates,polyoxyethylene octylphenylether, PEG-1000 cetyl ether, polyoxyethylenetridecyl ether, polypropylene glycol butyl ether, Poloxamer® 401,stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallowamide. Examples of amphoteric surfactants include sodiumN-dodecyl-.beta.-alanine, sodium N-lauryl-.beta.-iminodipropionate,myristoamphoacetate, lauryl betaine and lauryl sulfobetaine.

If desired, the tablets may also contain minor amounts of nontoxicauxiliary substances such as wetting or emulsifying agents, dyes, pHbuffering agents, or preservatives.

F. Modified Release Coatings

Compositions described herein, in the form of a solid dosage form, maybe coated with one or more immediate and/or modified release coatings,which further modulate the release of the active agent(s) from the coreor central layer. Suitable coatings include, but are not limited to,coatings which are soluble in, or permeable to, the acidic medium of thestomach (i.e. taste mask coatings and immediate release coatings);coatings which are insoluble in the acidic medium of the stomach but aresoluble in the neutral environment of the small intestine (i.e. entericcoatings); coatings which are insoluble in the stomach and theenvironment of the mid to the upper small intestine, but dissolve in thelower small intestine or upper large intestine (i.e. delayed releasecoatings); and combinations thereof. The dosage forms may also be coatedfor aesthetic reasons such as to impart a color to the dosage form or toapply a surface finish to the dosage form.

1. Immediate Release Coatings

Immediate release coatings are formed of a polymer that dissolves withinthe oral cavity upon contact with saliva or which are insoluble in theneutral pH4 of the oral cavity and which dissolve at the low pH of thestomach.

Coatings which dissolve in the mouth may have properties such asmucoadhesion, to prolong contact of the particles with the buccal,sublingual or other oral cavity surfaces to enhance uptake of the activeagent(s). Many mucoadhesive polymers are known and typically arecharacterized by a high density of carboxylic groups. See for example,U.S. Pat. No. 6,235,313 and U.S. Pat. No. 5,955,096 to Mathiowitz et al.

Coatings which dissolve in the stomach are typically used to provideproperties such as taste-masking. The cationic polymer Eudragit® E 100(Rohm Pharma) carries amino groups. Its films are, therefore, insolublein the neutral medium of saliva, but dissolve by salt formation in theacid environment of the stomach. Such film coatings with a thickness ofapproximately 10 micrometers can prevent medication with a bitter orunpleasant taste from dissolving in the mouth upon ingestion or duringswallowing. The protective film dissolves quickly under the acidicconditions in the stomach allowing for the active agent(s) to bereleased. The coating composition may include conventional additives,such as plasticizers, pigments, colorants, stabilizing agents, glidants,etc.

2. Sustained or Extended Release Coatings

Sustained or extended release of the active agent(s) is possible withthe use of a diffusion barrier coating on the drug-resin complexparticles. Suitable coating materials include, but are not limited to,cellulose polymers, such as cellulose acetate phthalate, hydroxypropylcellulose, hydroxypropyl methylcellulose phthalate and hydroxypropylmethylcellulose acetate succinate; polyvinyl acetate phthalate, acrylicacid polymers and copolymers, and methacrylic resins that arecommercially available under the trade name Eudragit t (Rohm Pharma),alginates, alkali-soluble acrylic resins, hydroxypropyl methylcellulosephthalate, methacrylate-methacrylic acid co-polymers, polyvinyl acetatephthalate, styrol maleic acid copolymers, copolymers available under thetrade name Eudragit® (Rohm Pharma), such aspoly(ethylacrylate-methylmethacrylate-triethylammonioethyl-metharylatechloride) (Eudragit® RS and Eudragit® RL) andpoly(ethylacrylate-methylmethacrylate) (Eudragit® NE), and combinationsthereof. Aqueous dispersions of such polymers are available under thetrade names Eudragit® RS 30 D, Eudragit® RL 30 D and Eudragit® NE 30 D.

These copolymers may be used alone, in admixture with each other, and inadmixture with plasticizers (for example, triethyl citrate), pigments,and other substances to alter the characteristics of the coating. Ingeneral, the major components of the coating should be insoluble in, andpermeable to, water. However, it may be desirable to incorporate awater-soluble substance, such as methyl cellulose, to alter thepermeability of the coating.

The coating materials may be applied as a suspension in an aqueousfluid. The coating composition may include conventional additives, suchas plasticizers, pigments, colorants, stabilizing agents, glidants, etc.A plasticizer is normally present to reduce the fragility of thecoating, and will generally represent about 10 wt. % to 50 wt. %relative to the dry weight of the polymer. Examples of typicalplasticizers are, but not limited to, polyethylene glycol, propyleneglycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutylphthalate, dibutyl sebacate, triethyl citrate, tributyl citrate,triethyl acetyl citrate, castor oil and acetylated monoglycerides. Astabilizing agent may be used to stabilize particles in the dispersion.Typical stabilizing agents are nonionic emulsifiers such as sorbitanesters, polysorbates and polyvinylpyrrolidone. Glidants are recommendedto reduce sticking effects during film formation and drying, and willgenerally represent approximately 25 wt. % to 100 wt, % of the polymerweight in the coating solution. One effective glidant is talc. Otherglidants such as magnesium stearate and glycerol monostearates may alsobe used. Pigments such as titanium dioxide may also be used. Smallquantities of an anti-foaming agent, such as a silicone (e.g.,simethicone), may also be added to the coating composition.

3. Enteric Coatings

Enteric coated dosage forms can be prepared as described in referencessuch as “Pharmaceutical dosage form tablets”, eds. Liberman et. al. NewYork, Marcel Dekker, Inc., 1989), “Remington—The science and practice ofpharmacy”, 20th ed., Lippincott Williams & Wilkins, Baltimore, Md.,2000, and “Pharmaceutical dosage forms and drug delivery systems”, 6thEdition, Ansel et.al., (Media, P A; Williams and Wilkins, 1995).Examples of suitable coating materials include but are not limited tocellulose polymers, such as cellulose acetate phthalate, hydroxypropylcellulose, hydroxypropyl methylcellulose phthalate and hydroxypropylmethylcellulose acetate succinate; polyvinyl acetate phthalate, acrylicacid polymers and copolymers, and methacrylic resins that arecommercially available under the trade name Eudragit 9 (Rohm Pharma).Additionally, the coating material may contain conventional carrierssuch as plasticizers, pigments, colorants, glidants, stabilizationagents, and surfactants.

III. METHOD OF MANUFACTURING

The compositions described herein can be prepared using techniques wellknown in the art. Multilayer tablets may be prepared by compressionmolding. In compression molding, the core and the one or more barrierlayers are prepared separately and then compressed using a multilayertableting press. Alternatively, the core could be prepared separatelywith the barrier layers added as a blend, and the composition compressedto form a tablet.

The geometric shape of the dosage forms described herein may varydepending on the type of release profile that is desired. In itssimplest form, the dosage form might consist of a monolithic core.Alternatively, the core may consist of one of more layers containing oneor more pharmaceutically active substances in each layer. Dosage formsof this type have been described in U.S. Pat. Nos. 5,626,874, 5,422,123and 6,027,748 to Conte et al.

Alternatively, one or more layers may contain no active agent(s). Eachlayer may contain the same or different release-controlling materialsand excipients. In another embodiment, the dosage form may be amultiparticulate system. Each particle may contain the same or differentpharmaceutically active substance and the same or differentrelease-controlling materials and other adjuvants. In a preferred dosageform, the core is multilayered, e.g. having two or three layers, one ormore of which contains active agent(s) and the other layers contain noactive agent(s). In a particularly preferred embodiment the dosage formcomprises a core consisting of three layers wherein an inner layercontains active agent(s) and the two outer layers do not contain activeagent(s).

The formulations can be coated with a film coat that at least partiallyovercoats the core using techniques well known in the art. The coatingscan be applied as a solid or as an aqueous suspension or organicsolution. Suitable techniques for applying the coating include, but arenot limited to, spray coating, pan coating, fluid bed coating, andcompression coating.

IV. METHODS OF ADMINISTRATION

The dosage forms described herein can be administered to treat a varietyof diseases or disorders. Although preferred patients are human,typically any mammal including domestic animals such as dogs and cats,may also be treated. The dosage forms are generally administered orallyin the form of a tablet or caplet. The dosage forms can be administeredin a single dose, an escalating dose, or administered at an elevateddosage which is then decreased to a lower dosage after a particularcirculating blood concentration of the active agent(s) has beenachieved. One of skill in the art would be able to choose administrationprotocols and determine appropriate dosing regimes based onbioavailability and half-life of the pharmaceutically active substanceto be administered. Appropriate dosages of the substance can bedetermined by one of skill in the art using routine experimentation andstandard techniques utilizing dosages currently approved, Intra-patientvariability is known in the art depending on the severity of symptomsand dosages are commonly adjusted to exact a particular therapeuticeffect in a particular patient.

For many of the disclosed active agent(s) appropriate dosage ranges havebeen established to maximize circulating concentrations of the substanceand minimize side-effects. Generally, the active agent can beadministered in amounts between about 0.001 to 100 mg/kg of body weight,preferably 0.01 to 10 mg/kg, more preferably 0.1 to 10 mg/kg. In thespecific case of calcium channel blockers, they can be administered at adosage of between about 0.001 to 100 mg/kg of body weight of thepatient, preferably 0.01 mg to 10 mg/kg, more preferably 0.1 to 1.0mg/kg. Preferred daily doses of a calcium channel blocker areapproximately 1-100 mg, preferably 2.5 mg to 50 mg to treatcardiovascular disorders such as hypertension, angina and cardiacarrhythmia.

By employing a mixture of enteric material(s) and hydrophilicmaterial(s) to form a release-controlling matrix one can obtain releaseprofiles characterized by the initial slow release of a drug substance,which over time as the dosage form descends in the GI tract, leads toincreasing release rates in response to changes in pH. Such releasesprofiles may be highly desirable when it is necessary to release themajority of the dose of an active substance in the lower GI tract. Bylower GI tract is meant the ileum and large intestine. The term “ileum”refers to the third part of the small intestine that continues to theduodenum and the jejunum. The term “large intestine” refers to a siteconsisting of the cecum, colon and rectum. The term “cecum” refers to ablind sack starting from the large intestine and in one end of which theileum opens.

The dosage forms described herein can be formulated to provide a varietyof pharmacokinetic release profiles designed to target the release ofactive agent(s) at a higher release rate at a particular absorption sitein the lower GI tract. As such, the use of these dosage forms maydiminish or eliminate unwanted side effects of many active agents. Theymay also render active agents efficacious, yet reduced in dose, comparedwith known formulations of those active substances.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

A. Pharmacokinetic Parameters

In one embodiment, the compositions described herein provide anincreased bioavailability (as measured by area under the drug plasmaconcentration-time curve (AUC)) as compared to the same dose of acalcium channel blocker, such as nisoldipine, in a reference formulationcontaining a slow release core and an immediate release coating(coat-core). In a preferred embodiment, the compositions provide anincrease in bioavailability of nisoldipine as compared to the same doseof drug in SULAR®. In another embodiment, the compositions contain areduced dose of nisoldipine, but exhibit a similar pharmacokineticprofile as SULAR®.

For example, a trilayer tablet containing 40 mg nisoldipine (FormulationA) exhibited a roughly 16% increase in the AUC_(last) compared to SULAR®40 mg. This suggests that the dose of nisoldipine in the trilayer tabletcan be reduced by approximately 15-17%, or 16% (i.e. to 34 mg) and stillprovide an effective amount of the drug. Accordingly, the 10 mg, 20 mg,30 mg, and 40 mg dosage strengths of SULAR® can be replaced withreduced, bioequivalent dosage strengths (for example, 8.5 mg, 17 mg,25.5 mg, and 34 mg). This may result in lower manufacturing costs due tothe lower doses required to obtain the desired therapeutic effect.

In another embodiment, the compositions described herein contain one ormore controlled release elements in an amount effective to provide acontrolled release of the calcium channel blocker, the compositionproviding a T_(max) of the calcium channel blocker from about 9 to about20 hours and an AUC_(last) of the calcium channel blocker from about 48to about 63 hr*ng/ml under fasting conditions based on a 40 mg dose.

In yet another embodiment, the compositions described herein contain oneor more controlled release elements in an amount effective to provide acontrolled release of the calcium channel blocker, the compositionproviding a T_(max) of the calcium channel blocker from about 9 to about20 hours and a Cmax of the calcium channel blocker from about 2.75 toabout 4 ng/mL under fasting conditions based on a 40 mg dose.

The present invention will be further understood by reference to thefollowing non-limiting examples.

EXAMPLES Example 1 Trilayer Tablets Containing 40 mg of Nisoldipine

Three different formulations, each of which contained 40 mg ofNisoldipine, were prepared. The formulations are identified asFormulation A, Formulation B, and Formulation C and are described inTables 1-3. Formulation C was coated with an enteric coating (5% weightgain) containing a combination of Eudragit® S100 (methacrylic acidcopolymer type B) and Eudragit® L100 (methacrylic acid copolymer typeA). Formulations A and B were coated with an OPADRY® II seal coatavailable from Colorcon, West Point, Pa. TABLE 1 Composition ofFormulation A First Second Barrier Barrier Weight Layer Core Layer Total% (of the Ingredient (mg/tab) (mg/tab) (mg/tab) (mg) tablet) Nisoldipine40.00 40.00 7.1 Lactose Monohydrate, NF 76.5 32.35 57.375 166.23 29.5Ferric Oxide, NF (yellow) 0.20 0.15 0.35 0.1 Hypromellose, USP, type2208 53.65 53.65 9.5 (Methocel ® K4M) Sodium lauryl sulfate, NF 50.0050.00 8.9 Methacrylic Acid Copolymer, 21.40 21.40 3.8 Type B, NF (S)Hypromellose Phthalate, NF 26.5 19.875 46.38 8.2 Glyceryl Behenate, NF36.8 27.6 64.40 11.4 Povidone, USP (29/32) 7.00 10.70 5.25 22.95 4.1Hypromellose, USP, type 2910 37.5 37.50 6.7 (Methocel ® E5)Hypromellose, USP, type 2910 50.0 50.0 8.9 (Methocel ® E50LV) MagnesiumStearate, NF 2.00 3.80 1.5 7.30 1.3 (vegetable) Colloidal SiliconDioxide, NF 1.00 1.10 0.75 2.85 0.5 Totals 200 213 150 563 100%

TABLE 2 Composition of Formulation B First Second Barrier Barrier WeightLayer Core Layer Total % (of the Ingredient (mg/tab) (mg/tab) (mg/tab)(mg) tablet) Nisoldipine 40.00 40.00 7.10 Lactose Monohydrate, NF 76.5032.35 57.375 166.23 29.52 Ferric Oxide, NF (yellow) 0.20 0.15 0.35 0.06Hypromellose, USP, type 53.65 53.65 9.53 2208 (Methocel ® K4M)Hypromellose, USP, type 76.50 57.375 133.88 23.78 2910 (Methocel ® E4M)Sodium lauryl sulfate, NF 50.00 50.00 8.88 Methacrylic Acid Copolymer,21.40 21.40 3.80 Type B, NF (S) Glyceryl Behenate, NF 36.80 27.60 64.4011.44 Povidone, USP (29/32) 7.00 10.70 5.25 22.95 4.08 MagnesiumStearate, NF 2.00 3.80 1.50 7.30 1.30 (vegetable) Colloidal SiliconDioxide, NF 1.00 1.10 0.75 2.85 0.51 Totals 200.00 213.00 150.00 563.00100%

TABLE 3 Composition of Formulation C First Second Weight Barrier BarrierFilm % (of layer Core layer Coat Total the Ingredient (mg/tab) (mg/tab)(mg/tab) (mg/tab) (mg) tablet) Nisoldipine 40.00 40.00 6.14 Lactose 76.532.35 57.375 166.23 25.53 Monohydrate, NF Ferric Oxide, NF 0.20 0.150.35 0.05 (yellow) Hypromellose, 53.65 53.65 8.24 USP, type 2208(Methocel ® K4M) Sodium lauryl 50.00 50.00 7.68 sulfate, NF MethacrylicAcid 21.40 25.45 46.85 7.20 Copolymer, Type B, NF (S) Hypromellose 26.519.875 46.38 7.12 Phthalate, NF Glyceryl Behenate, 36.8 27.6 64.40 9.89NF Povidone, USP 7.00 10.70 5.25 22.95 3.53 (29/32) Hypromellose, 37.537.50 5.76 USP, type 2910 (Methocel ® E5) Hypromellose, 50.0 50.00 7.68USP, type 2910 (Methocel ® E50LV) Magnesium 2.00 3.80 1.5 7.30 1.12Stearate, NF (vegetable) Colloidal Silicon 1.00 1.10 0.75 2.85 0.44Dioxide, NF Methacrylic Acid 25.49 25.49 3.92 Copolymer, Type A, NFTriethyl Citrate, 35.86 35.86 5.51 USP Potassium 1.21 1.21 0.19Hydroxide, NF Totals 200.00 213.00 150.00 88.00 651.00 100%

The formulations described above were prepared as follows:

Core or Central Layer

1. Nisoldipine and sodium lauryl sulfate were mixed in a high shearmixer for two minutes. Lactose monohydrate, povidone, methacrylic acidcopolymer (type B), and hypromellose type 2208 (Methocel K4M) were addedto the mixer and mixed for ten minutes.

2. The binding solution was prepared by dissolving povidone in purifiedwater and adding sodium lauryl sulfate. The mixture was mixed in asuitable tank and left to rest until defoaming was complete.

3. The binding solution was added to the high shear mixer containing themixture of step 1 and mixed briefly for two minutes. The resultinggranulation was kneaded and transferred to a fluid bed dryer and drieduntil an LOD below 2.5% was obtained. After drying, the granulation wasmilled with an oscillatory mill.

4. After milling, one half of the granulation was placed into adiffusion blender. Colloidal silicon dioxide was added to the blenderfollowed by the remainder of the granulation. The mixture was mixed fortwenty minutes.

5. Magnesium stearate was premixed manually with 5% of the mixture fromstep 4. The premix was added to the granulation in a diffusion blenderand mixed for ten minutes.

Barrier Layers

1. Lactose monohydrate, glyceryl behenate, ferric oxide (yellow),povidone, hypromellose type 2910 (Methocel E4M), and optionallyhypromellose phthalate, were added to a high shear mixer and mixed forsix minutes.

2. Purified water was added to the mixture in step 1 and kneaded forabout two minutes.

3. The granulation was transferred to a fluid bed dryer and dried untilan LOD below 2.5% was obtained. After drying, the granulation was milledon an oscillatory mill.

4. After milling, one half of the granulation was placed into adiffusion blender. Colloidal silicon dioxide was added to the blenderfollowed by the remainder of the granulation. The mixture was mixed fortwenty minutes.

5. Magnesium stearate was premixed manually with 5% of the mixture fromstep 4. The premix was added to the granulation in a diffusion blenderand mixed for ten minutes.

Tableting

The central layer and the barrier layers were loaded into a HATAmulti-layer tablet press and pressed to form the trilayer tablets.

Film Coat (Formulations A and B)

The film coatings are applied at a target of 5% weight gain on a 563 mgtablet. Opadry® II film coating compositions were obtained fromColorcon, West Point Pa. Four different coating compositions were used:49B97383 Beige, 49B97382 Beige, 49B92439 Yellow, and 49B97379 Beige. Allof the film coat compositions contain polydextrose FCC, HPMC2910/hypromellose 3 cP, HPMC 2910/hypromellose 6 cP, titanium dioxide,HPMC 2910/hypromellose 15 cP, macrogol/PEG, iron oxide yellow, andcarnauba wax. The coating compositions vary in the presence or absenceof iron oxide black, iron oxide red, and FD&C yellow #5/TartrazineAluminum Lake. The tablets were coated as directed by the manufacturer.

Enteric Coating (Formulation C)

1. Potassium hydroxide was dissolved in purified water with agitation toform a 1N solution.

2. Methacrylic acid copolymer type B (Eudragit S100) was added slowly toa vortex of purified water and mixed until dissolved.

3. The 1N potassium hydroxide solution of step 1 was added to thesolution of step 2 and the mixture was stirred gently.

4. Triethyl citrate was added to the solution of step 3 and stirreduntil the mixture was homogeneous.

5. Steps 1-4 were repeated using methacrylic acid copolymer type A(Eudragit L100) to form a homogeneous mixture.

6. The solution of step 4 was added to a mixing vessel and stirredslowly. The solution of step 5 was added to the vessel and the mixturewas stirred for the required period of time.

7. The tablets of Formulation C were coated with the coating layer usinga Glatt pan coater.

Example 2 Relative Bioavailability Study of Nisoldipine 40 mg ExtendedRelease Tablets Under Fasting Conditions

The pharmacokinetic parameters of formulations A-C described in Example1 were compared to those of a reference formulation (Formulation D). Thereference formulation was SULAR® Nisoldipine Extended Release (40 mg).SULAR® is a coat-core formulation consisting of a core containingNisoldipine, coated with an immediate release coating which alsocontains Nisoldipine. The components of SULAR®, and theirconcentrations, are given in Table 4.

The objective of this single-dose, open-label, randomized study was tocompare, under fasting conditions, the rate of absorption and oralbioavailability of a test formulation of nisoldipine 40 mgextended-release tablets described in Example 1 to an equivalent oraldose of the commercially available reference product, Sular® 40 mgextended-release tablets, when administered to healthy subjects. TABLE 4Composition of SULAR ® (Formulation D) Film Coat Core Coat Total Weight% (of Ingredient (mg/tab) (mg/tab) (mg/tab) (mg/tab) the tablet)Nisoldipine 32.0 8.0 40.0 12.27 Crospovidone, NF 5.0 5.0 1.53 Lactose87.5 4.0 91.5 28.07 Monohydrate, NF Magnesium Stearate, 1.0 0.2 1.2 0.37NF Corn Starch, NF 10.0 10.0 3.07 Microcrystalline 17.2 17.2 5.28Cellulose, NF Povidone, USP 1.8 1.8 0.55 Sodium lauryl 0.8 0.8 0.25sulfate, NF Hydroxypropyl- 84.5 84.5 25.92 cellulose, medium viscosity,NF Hydroxypropyl- 63.0 63.0 19.33 cellulose, low viscosity, NFHypromellose, USP 6.6 6.6 2.02 Ferric Oxide, NF 0.11 0.11 0.03 (red)Ferric Oxide, NF 0.99 0.99 0.30 (yellow) Macrogol, NF 2.2 2.2 0.67Titanium Dioxide, 1.1 1.1 0.34 USP Totals 268.0 47.0 11.0 326.00 100.00

Thirty-two healthy adults participated in the comparison of the threeformulations of nisoldipine 40 mg tablets described in Example I versusSULAR®. 31 subjects completed the study. Subjects received the assignedtreatment during the first period and received the alternate treatmentduring the subsequent periods according to the randomization scheme.Dosing days were separated by a washout period of at least 7 days. Anequal number of subjects were randomly assigned to each possiblesequence of treatments. Drug administration consisted of an oral dose ofthe formulations described in Example 1 and SULAR® under fastingconditions.

Blood samples were drawn prior to dosing (pre-dose) at 1, 1.5, 2, 3, 4,6, 7.5, 9, 10.5, 12, 14, 16, 18, 20, 21, 23, 24, 26, 28, 30, 36, and 48hours post-dose.

Plasma samples were analyzed by CEDRA Corporation using a validatedLC-MS-MS procedure with a lower limit of quantification of 0.0150 ng/mLfor nisoldipine. Data were stored in the Watson LIMS System (ThermioElectron Corporation Version 6.4.0.02).

Data from all subjects who completed the study were to be included inthe pharmacokinetic and statistical analyses. The concentration-timedata were transferred from Watson directly to WinNonlin (EnterpriseVersion 4.0, Pharsight, Cary, N.C.) using the Custom Query Builderoption for analysis. Data were analyzed by non-compartmental methods inWinNonlin. Concentration-time data that were BLQ (<0.0150 ng/mL) weretreated as zero (0.00 ng/mL) in the data summarization and descriptivestatistics. In the pharmacokinetic analysis, BLQ concentrations weretreated as zero from time-zero up to the time at which the firstquantifiable concentration was observed; embedded and/or terminal BLQconcentrations were treated as “missing”. Full precision concentrationdata were used for all pharmacokinetic and statistical analyses.

The following pharmacokinetic parameters were calculated for eachsubject and period: peak concentration in plasma (C_(max)), time to peakconcentration (T_(max)), elimination rate constant (λ_(z)), terminalhalf-life (T_(1/2)), area under the concentration-time curve fromtime-zero to the time of the last quantifiable concentration(AUC_(last)), and area under the plasma concentration time curve fromtime-zero extrapolated to infinity (AUC_(inf)), and are shown in Table5. Formulation A was chosen for further testing.

A comparison of the pharmacokinetic parameters for Formulation A and thereference formulation (Formulation D) are shown in Table 6. Table 7shows the statistical analysis of the non-transformed pharmacokincticparameters of nisoldipine after Formulation A and the reference product(Formulation D).

Analysis of variance (ANOVA) and the Schuirmann's two one-sided t-testprocedures at the 5% significance level were applied to thelog-transformed pharmacokinetic exposure parameters, C_(max),AUC_(last), and AUC_(inf). The 90% confidence interval for thedifference between the means of the test product and the referenceproduct was calculated. Bioequivalence was declared if the lower andupper confidence intervals of the log-transformed parameters were within80%-125%. TABLE 5 Pharmacokinetic Parameters of Nisoldipine After OralAdministration Treatment A: Treatment B: Treatment C: Treatment D: TestFormulation A Test Formulation B Test Formulation C Reference ProductParameter n Mean SD CV % n Mean SD CV % n Mean SD CV % n Mean SD CV %T_(max) (hr) 31 9.42 5.57 59.16 31 16.44 9.49 57.71 31 20.57 9.47 46.0532 8.12 7.34 90.47 T_(lag) (hr) 31 0.03 0.18 556.78 31 3.31 4.03 122.0031 0.00 0.00 NC 32 0.13 0.71 565.69 C_(max) 31 4.03 2.51 62.22 31 2.831.13 39.96 31 2.75 1.47 53.54 32 3.49 1.52 43.42 (ng/mL) AUC_(last) 3162.61 24.53 39.18 31 48.92 24.65 50.39 31 51.86 30.68 59.16 32 53.4623.26 43.51 (hr * ng/mL) AUC_(inf) 29 72.84 30.97 42.52 26 61.28 34.2755.93 25 56.11 36.51 65.07 30 68.21 43.33 63.52 (hr * ng/mL)AUC_(Extrap) 29 12.17 11.27 92.55 26 12.64 13.45 106.43 25 11.94 14.26119.38 30 14.00 15.84 113.11 (%) λ_(z) (hr⁻¹) 29 0.0600 0.0247 41.06 260.0691 0.0337 48.78 25 0.0739 0.0299 40.53 30 0.0580 0.0238 41.02T_(1/2) (hr) 29 14.23 8.83 62.01 26 12.92 8.89 68.83 25 12.78 11.2087.63 30 17.57 18.77 106.82 T_(last) (hr) 31 48.07 0.26 0.54 31 48.040.06 0.12 31 47.09 3.84 8.16 32 48.03 0.08 0.17 C_(last) 31 0.470 0.37078.77 31 0.491 0.441 89.67 31 0.532 0.533 100.15 32 0.441 0.408 92.39(ng/mL) MRT (hr) 29 25.40 12.19 47.98 26 28.45 13.68 48.08 25 27.8916.00 57.37 30 28.61 24.66 86.18

TABLE 6 Pharmacokinetic Parameters of Nisoldipine After OralAdministration Treatment A: Treatment D: Test Formulation #1 ReferenceProduct Parameter n Mean SD CV % n Mean SD CV % T_(max) (hr) 31 9.425.57 59.16 32 8.12 7.34 90.47 T_(lag) (hr) 31 0.03 0.18 556.78 32 0.130.71 565.69 C_(max) (ng/mL) 31 4.03 2.51 62.22 32 3.49 1.52 43.42AUC_(last) 31 62.61 24.53 39.18 32 53.46 23.26 43.51 (hr * ng/mL)AUC_(inf) (hr * ng/mL) 29 72.84 30.97 42.52 30 68.21 43.33 63.52AUC_(Extrap) (%) 29 12.17 11.27 92.55 30 14.00 15.84 113.11 λ_(z) (hr⁻¹)29 0.0600 0.0247 41.06 30 0.0580 0.0238 41.02 T_(1/2) (hr) 29 14.23 8.8362.01 30 17.57 18.77 106.82 T_(last) (hr) 31 48.07 0.26 0.54 32 48.030.08 0.17 C_(last) (ng/mL) 31 0.470 0.370 78.77 32 0.441 0.408 92.39 MRT(hr) 29 25.40 12.19 47.98 30 28.61 24.66 86.18

TABLE 7 Statistical Analysis of the Non-Transformed PharmacokineticParameters of Nisoldipine After Formulation A and the Reference ProductRatio (%) 90% Confidence Dependent Least Squares Mean (Test/ IntervalVariable Test Reference Reference) Lower Upper Power C_(max) 4.01763.4943 114.98 96.07 133.89 0.5385 AUC_(last) 62.1910 53.4555 116.34102.23 130.46 0.7550 AUC_(inf) 67.0708 63.9262 104.92 80.56 129.280.3847 T_(max) 9.3247 8.1156 114.90 77.51 152.29 0.2270 T_(lag) 0.02520.1250 20.19 −659.85 700.23 0.1004 λ_(z) 0.0651 0.0644 100.99 83.73118.25 0.6044 T_(1/2) 11.9103 14.3679 82.90 55.16 110.63 0.3241 MRT22.5857 24.0788 93.80 70.83 116.77 0.4161

TABLE 8 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of Nisoldipine after Test Formulation #1 and ReferenceProduct LS Geometric Dependent Mean^(a) Mean^(b) Ratio (%)^(c) 90%CI^(d) ANOVA Variable Test Ref Test Ref (Test/Ref) Lower Upper Power CV% ln (C_(max)) 1.2424 1.1624 3.4639 3.1975 108.33 90.47 129.72 0.653744.97 ln (AUC_(last)) 4.0571 3.8763 57.8035 48.2441 119.81 100.89 142.290.6894 42.68 ln (AUC_(inf)) 4.1247 3.9602 61.8507 52.4682 117.88 90.92152.85 0.4087 54.05^(a)Least Squares Mean for the Test Formulation #1 (Test) and ReferenceProduct (Ref)^(b)Geometric Mean based on LS Mean of log-transformed parameter values^(c)Ratio (%) = Geometric Mean (Test)/Geometric Mean (Ref)^(d)90% Confidence IntervalNote:Statistical analysis based n = 31 for C_(max), AUC_(last) and n = 21 forAUC_(inf)

Example 3 Relative Bioavailability Study of Nisoldipine 40 mg ExtendedRelease Tablets Under Fed Conditions

The objective of this study was to compare the food effect of theFormulation A described in Example versus the food effect of the Sular®market formulation. To determine the food effects for Formulation A andSular, the pharmacokinetic data for these two formulations from Example2 under fasting conditions were used as a reference. The same 32subjects from Example 2 were enrolled in the food effect study.

Twenty-six (26) subjects completed the study. In the first period,subjects received the assigned treatment and received the alternatetreatment during the subsequent period according to the randomizationscheme. Dosing days were separated by a washout period of at least 7days. An equal number of subjects were randomly assigned to eachpossible sequence of treatments. Blood samples were taken and analyzedas described in Example 2. Table 9 shows pharmacokinetic data forFormulation A (Treatment E) and the reference formulation (Sular, 40 mgextended-release) under fed conditions. Table 10 shows analysis of thenon-transformed pharmacokinetic parameters of nisoldipine after testformulation A (Treatment E) and reference product (Treatment F) underfed conditions. Table 11 shows statistical analysis of thelog-transformed systemic parameters of nisoldipine after testformulation A (Treatment E) and the reference product (Treatment F)under fed conditions. TABLE 9 Statistical Analysis of theNon-Transformed Pharmacokinetic Parameters of Nisoldipine after TestFormulation #1 (Treatment E) and Reference Product (Treatment F) underFed Conditions Ratio (%) 90% Confidence Dependent Least Squares Mean(Test/ Interval Variable Test Reference Reference) Lower Upper PowerC_(max) 9.0795 10.1485 89.47 63.66 115.27 0.3547 AUC_(last) 46.735849.9013 93.66 77.56 109.75 0.6596 AUC_(inf) 48.9166 52.8817 92.50 77.06107.95 0.6910 T_(max) 6.1372 6.2904 97.56 81.34 113.79 0.6534 T_(lag)0.0769 0.1154 66.67 −65.04 198.37 0.1101 λ_(z) 0.0547 0.0539 101.3291.40 111.25 0.9523 T_(1/2) 13.2983 14.6139 91.00 75.23 106.76 0.6754MRT 13.6435 16.3926 83.23 67.60 98.85 0.6822

TABLE 10 Statistical Analysis of the Non-Transformed PharmacokineticParameters of Nisoldipine after Test Formulation A (Treatment E) andReference Product (Treatment F) under Fed Conditions Least Squares MeanRatio 90% Confidence Dependent Treatment Treatment (%) Interval VariableE F (E/F) Lower Upper Power C_(max) 9.0795 10.1485 89.47 63.66 115.270.3547 AUC_(last) 46.7358 49.9013 93.66 77.56 109.75 0.6596 AUC_(inf)48.9166 52.8817 92.50 77.06 107.95 0.6910 T_(max) 6.1372 6.2904 97.5681.34 113.79 0.6534 T_(lag) 0.0769 0.1154 66.67 −65.04 198.37 0.1101λ_(z) 0.0547 0.0539 101.32 91.40 111.25 0.9523 T_(1/2) 13.2983 14.613991.00 75.23 106.76 0.6754 MRT 13.6435 16.3926 83.23 67.60 98.85 0.6822

TABLE 11 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of Nisoldipine after Test Formulation #1 (Treatment E) andthe Reference Product (Treatment F) under Fed Conditions Ratio DependentLS Mean^(a) Geometric Mean^(b) (%)^(c) 90% CI^(d) ANOVA VariableTreatment E Treatment F Treatment E Treatment F (E/F) Lower Upper PowerCV % ln (C_(max)) 2.1192 2.0365 8.3246 7.6641 108.62 87.54 134.78 0.523947.94 ln (AUC_(last)) 3.7901 3.7689 44.2614 43.3308 102.15 90.67 115.080.9256 25.53 ln (AUC_(inf)) 3.8330 3.8390 46.2024 46.4782 99.41 88.59111.55 0.9389 24.65

Example 4 Trilayer Tablets Containing a Nisoldipine Core and Two BarrierLayers

Table 5 shows that the AUC_(last) for formulation A is approximately 17%higher than the AUC_(last) for the reference formulation having the samedosage of nisoldipine. This suggests that the dose of nisoldipine informulation A can be reduced by approximately 16% and still exhibit apharmacokinetic profile similar to the reference formulation.

Formulations containing 8.5, 17, 25.5, and 34 mg of Nisoldipine in thecore were prepared based on the procedures described in Example 1. Thesedosages represent approximately 16% less than 10 mg, 20 mg, 30 mg, and40 mg, respectively. The components of each formulation, and theirconcentrations, are shown in Tables 10-13. TABLE 12 NisoldipineMultilayer Tablet Formulations 04B4 barrier 8.5 mg 17 mg Prototype BPrototype A 25.5 mg 34 mg Ingredients mg/tab % mg/tab % mg/tab % mg/tab% Methocel E5 17.50 25.00 25.00 25.00 37.50 25.00 37.50 25.00 HPMCPhthalate 9.28 13.25 13.25 13.25 19.88 13.25 19.88 13.25 HP50 Lactosepulvis 26.85 38.35 38.35 38.35 57.53 38.35 57.53 38.35 H2O Compritol 88812.88 18.40 18.40 18.40 27.60 18.40 27.60 18.40 ATO Plasdone K29-32 2.453.50 3.50 3.50 5.25 3.50 5.25 3.50 Mg stearate 0.70 1.00 1.00 1.00 1.501.00 1.50 1.00 Aerosil 200 0.35 0.50 0.50 0.50 0.75 0.50 0.75 0.50 Total70.00 100.00 100.00 100.00 150.00 100.00 150.00 100.00 Core (ActiveLayer) Ingredients mg/tab % mg/tab % mg/tab % mg/tab % Nisoldipine 8.5012.07 17.00 12.07 25.50 11.97 34.00 15.96 Lactose H2O 14.44 20.51 52.4437.24 76.02 35.69 48.00 22.54 Methocel K4M 27.18 38.61 30.80 21.88 42.6020.00 51.50 24.18 Eudragit S100 5.35 7.60 10.70 7.60 21.40 10.05 21.4010.05 Plasdone 2.68 3.80 5.35 3.80 10.70 5.02 10.70 5.02 Sodium Lauryl10.63 15.09 21.25 15.09 31.88 14.97 42.50 19.95 Sulfate Magnesium 1.261.78 2.51 1.78 3.80 1.78 3.80 1.78 stearate Aerosil 200 0.38 0.53 0.750.53 1.10 0.52 1.10 0.52 Total 70.40 100.00 140.80 100.00 213.00 100.00213.00 100.00 01B4 barrier Ingredients mg/tab % mg/tab % mg/tab % mg/tab% Methocel E50 22.50 25.00 25.00 25.00 50.00 25.00 50.00 25.00 HPMCPhthalate 11.93 13.25 13.25 13.25 26.50 13.25 26.50 13.25 HP50 Lactosepulvis 34.52 38.35 38.35 38.35 76.70 38.35 76.70 38.35 H2O Compritol 88816.56 18.40 18.40 18.40 36.80 18.40 36.80 18.40 ATO Plasdone K29-32 3.153.50 3.50 3.50 7.00 3.50 7.00 3.50 Mg stearate 0.90 1.00 1.00 1.00 2.001.00 2.00 1.00 Aerosil 200 0.45 0.50 0.50 0.50 1.00 0.50 1.00 0.50 Total90.00 100.00 100.00 100.00 200.00 100.00 200.00 100.00 Total tablet230.40 340.80 563.00 563.00 weight, uncoated mg/ % wt mg/ % wt mg/ % wtmg/ % wt tablet gain tablet gain tablet gain tablet gain Opadry IIBeige, 11.52 5.00 — — — — — — 49B97383 Opadry II — — 7.04 5.00 — — — —Yellow, 49B92439 Opadry II Beige, — — — — 28.15 5.00 — — 49B97382 OpadryII Beige, — — — — — — 28.15 5.00 49B97379 Total tablet 241.92 — 347.84 —591.15 — 591.15 — weight, coated mg/ mg/ mg/ mg/ tablet tablet tablettablet Opacode Black 0.20 0.20 0.33 0.33 (S-1-27794) Total tablet 242.12348.04 591.4 591.48 weight, coated, imprinted

Example 5 Bioequivalence of Lower Dose Sular® Geomatrix (34 mgnisoldipine) with Sular® (40 mg Nisoldipine)

The bioequivalence of 34 mg nisoldipine Sular® Geomatrix® (i.e.,Geomatrix) with 40 mg nisoldipine Sular® was confirmed with asingle-dose, open-label, randomized, four-period, two-treatment,two-sequence replicate design crossover study. The study compared therate of absorption and oral bioavailability of a test formulation,Geomatrix® 16-E, 34 mg tablets (Treatment E) versus that of thereference product, Sular® 40 mg tablets (Treatment F) following anovernight fast of at least 10 hours.

Study Design

This was a pivotal, single-dose, open-label, randomized, four-period,two-treatment, two-sequence replicate-design crossover study in whichfifty-two (52) healthy adult subjects were scheduled to receive fourseparate single-dose administrations of nisoldipine extended-releasetablets in four study periods following an overnight fast of at least 10hours. Attempts were made to enroll an equal number of male and femalesubjects. Subjects who successfully completed the screening processchecked into the research center the night before dosing. Subjects whocontinued to meet inclusion/exclusion criteria the morning of dose wereassigned a subject number, based on the order in which they successfullycompleted the screening process and procedures as outlined in the studyprotocol. Dosing days were separated by a washout period of at least 7days.

Subjects received each of the treatments listed below twice in a2-sequence randomized fashion during the four treatment periods. Testproduct “Treatment E” is Geomatrix® 16-E nisoldipine extended-releasetablet administered in one 34 mg tablet. Reference product “Treatment F”is Sular® extended-release tablet administered in one 40 mg tablet.

Clinical Procedures Summary

During each study period, 6 mL blood samples were obtained prior to eachdosing and following each dose at selected times through 36 hourspost-dose. Two 6 mL blood samples were obtained at 48, 60, and 72 hourspost-dose. A total of 96 PK blood samples were to be collected from eachsubject, 24 samples in each of four separate study periods.

In addition, blood was drawn and urine was collected for clinicallaboratory testing (blood chemistries, hematology and urinalysis) atscreening, baseline (Period 1 check-in), and at end-of-study discharge(72-hour procedures at Period 4). In addition, blood was drawn atcheck-in the evening before dosing in each of Periods 2, 3, and 4 forhematocrit and hemoglobin evaluations, which were reviewed by theInvestigator prior to dosing in each of the three periods. Forty-nine(49) of the 52 subjects enrolled completed at least two periods of thestudy.

Procedures for Collecting Samples for Pharmacokinetic Analysis

Blood samples (1×6 mL, 2×6 mL) were collected in vacutainer tubescontaining K₂-EDTA as a preservative at pre-dose (0) and at 1.0, 2.0,3.0, 4.0, 5.0, 6.0, 7,5, 9.0, 10.5, 12.0, 14.0, 18.0, 24.0, 26.0, 28.0,30.0, 36.0, 48.0, 60.0, and 72.0 hours after dosing during each studyperiod.

Bioanalytical Summary

Plasma samples were analyzed for nisoldipine by CEDRA Corporation usingvalidated LC-MS-MS procedures. The methods were validated for ranges of0.0150 to 10.0 ng/mL and 1.00 to 100 pg/mL, based on the analysis of0.250 mL and 1.00 mL of plasma, respectively.

Pharmacokinetic Analysis

Data from 49 subjects who successfully completed at least two studyperiods (one test, one reference) without protocol violation wereincluded in the pharmacokinetic and statistical analyses. Three subjectsdid not complete the study; samples from these subjects were notanalyzed. Two subjects experienced emesis during the study; thesesubjects were determined to be not evaluable for the period(s) in whichemesis occurred during this comparative study of extended-releasenisoldipine formulations. Although concentration-time data were acquiredand retained in the data listing, data for one subject in Period 2(Treatment E) and one subject in Period 4 (Treatment E) were excludedfrom the pharmacokinetic analysis set.

Concentration-time data were transferred from Watson LIMS directly toWinNonlin Enterprise Edition (Version 4.0, Pharsight Corporation) usingthe Custom Query Builder option for analysis. Data were analyzed bynoncompartmental methods in WinNonlin. Concentration-time data that werebelow the limit of quantification (BLQ) were treated as zero in the datasummarization and descriptive statistics. In the pharmacokineticanalysis, BLQ concentrations were treated as zero from time-zero up tothe time at which the first quantifiable concentration was observed;embedded and/or terminal BLQ concentrations were treated as “missing.”Full precision concentration data (not rounded to three significantfigures) and actual sample times were used for all pharmacokinetic andstatistical analyses.

The following pharmacokinetic parameters were calculated: peakconcentration in plasma (C_(max)), time to peak concentration (T_(max)),elimination rate constant (λ_(z)), terminal half-life (T_(1/2)), areaunder the concentration-time curve from time-zero to the time of thelast quantifiable concentration (AUC_(last)), and area under the plasmaconcentration time curve from time-zero extrapolated to infinity(AUC_(inf)).

Analysis of a linear mixed effect and the Schuirmann's two one-sidedt-test procedures at the 5% significance level were applied to thelog-transformed pharmacokinetic exposure parameters, C_(max),AUC_(last), and AUC_(inf). The 90% confidence interval for the ratio ofthe geometric means (Test/Reference) was calculated. Bioequivalence wasdeclared if the lower and upper confidence intervals of thelog-transformed parameters were within 80% to 125%.

Results

Plasma concentration-time data and pharmacokinetic parameters weresummarized by treatment. Since subjects were scheduled to receive eachtreatment on two occasions, descriptive statistics by treatment arebased on 93 to 95 observations. Quantifiable pre-dose concentrationswere observed for some subjects. However, since the pre-doseconcentrations were well below 5% of C_(max) for these subjects after agiven treatment, the pre-dose concentrations were included in allpharmacokinetic analyses without adjustment.

The pharmacokinetic data and statistical analyses are shown below inTable 13 and Table 14, Due to the presence of secondary peaks andvariability in the terminal phase of some individual profiles, lambda-z(λ_(z)) was estimated via linear regression of log concentration versustime data in WinNonlin. The data points that were included in thecalculation were based on the regression with the largest adjusted R²value. This default estimation of λ_(z) was used throughout this studyfor all pharmacokinetic analyses.

Conclusions

The 90% confidence interval for comparing the maximum exposure, based onln(C_(max)), is within the accepted 80% to 125% limits. The 90%confidence intervals for comparing total systemic exposure, based onln(AUC_(last)) and ln(AUC_(inf)), are within the accepted 80% to 125%limits. Therefore, the test formulation of Geomatrix® 16-E, 34 mgtablets is bioequivalent to the reference product, Sular® 40 mg tablets,under fasting conditions. TABLE 13 Pharmacokinetic Parameters ofNisoldipine after Administration of Test Formulation 16-E (Geomatrix,Treatment E) and the Reference Product (Sular, Treatment F) Treatment E:Treatment F: Test Formulation 16-E Reference Product (Geomatrix) (Sular)Parameter n Mean SD CV % n Mean SD CV % T_(max) (hr) 93 9.22 5.13 55.6195 8.49 7.79 91.84 C_(max) (ng/mL) 93 3.79 3.56 93.97 95 3.58 3.05 85.08AUC_(last) 93 62.35 69.30 111.15 95 60.10 31.52 52.45 (hr * ng/mL)AUC_(inf) 93 65.24 74.67 114.46 95 65.45 36.41 55.63 (hr * ng/mL)AUC_(Extrap) (%) 93 3.84 3.41 88.68 95 6.43 8.77 136.33 λ_(z) (hr⁻¹) 930.0554 0.0163 29.38 95 0.0527 0.0205 38.91 T_(1/2) (hr) 93 13.68 4.2531.05 95 17.08 13.74 80.49 T_(last) (hr) 93 72.00 0.00 0.00 95 72.000.01 0.01 C_(last) (ng/mL) 93 0.126 0.239 190.21 95 0.148 0.166 111.91Note:Full precision data used in pharmacokinetic analysis

TABLE 14 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of Nisoldipine Comparing Test Formulation 16-E (Geomatrix,Treatment E) to the Reference Product (Sular, Treatment F) DependentGeometric Mean^(a) Ratio (%)^(b) 90% CI^(c) Variable Test Ref (Test/Ref)Lower Upper Power ln (C_(max)) 3.0723 2.9941 102.61 93.61 112.47 0.9899ln (AUC_(last)) 50.7356 54.6492 92.84 87.77 98.20 1.0000 ln (AUC_(inf))52.7416 58.7395 89.79 84.37 95.56 1.0000^(a)Geometric Mean for the Test Formulation (Test) and Reference Product(Ref) based on Least Squares Mean of log-transformed parameter values^(b)Ratio(%) = Geometric Mean (Test)/Geometric Mean (Ref)^(c)90% Confidence Interval

FIG. 2 shows the mean nisoldipine concentration time profiles afteradministration of test formulation 16-E (Sular Geomatrix-Formulation E,34 mg nisoldipine) and the referenced product (Sular, Formulation F, 40mg nisoldipine).

Example 6 Bioequivalence of Lower Dose Sular Geomatrix (8.5 mgNisoldipine) with Sular (10 mg Nisoldipine)

The bioequivalence of 8.5 mg nisoldipine Sular® Geomatrinx® with 10 mgnisoldipine Sular® was confirmed with a single-dose, open label,randomized, four period, two-treatment, two-sequence replicate designcrossover study. The study compared the rate of absorption and oralbioavailability of a test formulation, Geomatrix® 16-E, 8.5 mgnisoldipine tablets (Treatment G) versus that of the reference product,Sular® 10 mg nisoldipine tablets (Treatment H) following an overnightfast of at least 10 hours.

This was a pivotal, single-dose, open-label randomized, four-period,two-treatment, two-sequence replicate-design crossover study in whichfifty-two (52) healthy adult subjects were scheduled to receive fourseparate single-dose administrations of nisoldipine extended-releasetablets in four study periods following an overnight fast of at least 10hours. Attempts were made to enroll an equal number of male and femalesubjects. Subjects who continued to meet inclusion/exclusion criteriathe morning of dose were assigned a subject number, based on the orderin which they successfully completed the screening process andprocedures as outlined in the study protocol. Dosing days were separatedby a washout period of at least 7 days.

Subjects received each of the treatments listed below twice in a2-sequence randomized fashion during the four treatment periods. Testproduct “Treatment G” is Geomatrix® nisoldipine extended-release tabletadministered in one 8.5 mg tablet. Reference product “Treatment A” isSular® extended-release tablet administered in one 10 mg tablet.

Clinical Procedures Summary

During each study period, one 6 mL blood sample was obtained within 60minutes prior to each dose administration and following each dose atselected times through 36 hours post-dose. Two 6 mL blood samples wereobtained at 48, 60, and 72 hours post-dose. A total of 96 PK bloodsamples were to be collected from each subject, 24 samples in each offour separate study periods. Forty-Nine (49) of the 52 subjects enrolledcompleted at least two periods of the study.

Procedures for Collecting Samples for Pharmacokinetic Analysis

Blood samples (1×6 mL, 2×6 mL) were collected in vacutainer tubescontaining K₂-EDTA as a preservative at pre-dose (0) and at 1.0, 2.0,3.0, 4.0, 5.0, 6.0, 7.5, 9.0, 10.5, 12.0, 14.0, 18.0, 24.0, 26.0, 28.0,30.0, 36.0, 48.0, 60.0, and 72.0 hours after dosing during each studyperiod.

Bioanalytical Summary

Plasma samples were analyzed for nisoldipine by CEDRA Corporation usingvalidated LC-MS-MS procedures. The methods were validated for ranges of0.0 150 to 10.0 ng/mL and 1.00 to 100 pg/mL, based on the analysis of0.250 mL and 1.00 mL of plasma, respectively.

Pharmacokinetic Analysis

Data from 49 subjects who successfully completed at least the first twoor at least the last two periods of the study (one test, one reference)without protocol violation were included in the pharmacokinetic andstatistical analyses. Subject 501 experienced emesis in one studyperiod. Although concentration-time data were acquired and retained inthe data listing, this subject was determined to be not evaluable forall study periods and was excluded from the pharmacokinetic data set forthe period(s) in which emesis occurred.

Concentration-time data were transferred from Watson LIMS directly toWinNonlin Enterprise Edition (Version 4.0, Pharsight Corporation) usingthe Custom Query Builder option for analysis. Data were analyzed bynoncompartmental methods in WinNonlin. Concentration-time data that werebelow the limit of quantification (BLQ) were treated as zero in the datasummarization and descriptive statistics. In the pharmacokineticanalysis, BLQ concentrations were treated as zero from time-zero up tothe time at which the first quantifiable concentration was observed;embedded and/or terminal BLQ concentrations were treated as “missing.”Full precision concentration data (not rounded to three significantfigures) and actual sample times were used for all pharmacokinetic andstatistical analyses.

The following pharmacokinetic parameters were calculated: peakconcentration in plasma (C_(max)), time to peak concentration (T_(max)),elimination rate constant (λ_(z)), terminal half-life (T_(1/2)), areaunder the concentration-time curve from time-zero to the time of thelast quantifiable concentration (AUC_(last)), and area under the plasmaconcentration time curve from time-zero extrapolated to infinity(AUC_(inf)).

Linear mixed-effects model procedures and the Schuirmann's two one-sidedt-test procedures at the 5% significance level were applied to thelog-transformed pharmacokinetic exposure parameters, C_(max),AUC_(last), and AUC_(inf). The 90% confidence interval for the ratio ofthe geometric means (Test/Reference) was calculated. Bioequivalence wasdeclared if the lower and upper confidence intervals of thelog-transformed parameters were within 80% to 125%.

Results

Plasma concentration-time data and pharmacokinetic parameters weresummarized by treatment. Since subjects were scheduled to receive eachtreatment on two occasions, descriptive statistics by treatment arebased on 96 or 94 observations. Mean concentration-time data are shownin FIG. 3. Results of the pharmacokinetic and statistical analyses areshown below in Table 15 and Table 16.

CONCLUSIONS

The 90% confidence interval for comparing the maximum exposure, based onln(C_(max)), is within the accepted 80% to 125% limits. The 90%confidence intervals for comparing total systemic exposure, based onln(AUC_(last)) and ln(AUC_(inf)), are within the accepted 80% to 125%limits. Therefore, the test formulation, Geomatrix 8.5 mg tablets, isbioequivalent to the reference product, Sular extended-release 10 mgtablets, under fasting conditions. TABLE 15 Pharmacokinetic Parametersof Nisoldipine after Administration of Test Formulation 16-E (Geomatrix,Treatment A) and the Reference Product (Sular, Treatment B) Treatment G:Treatment H: Test Formulation 2B Reference Product (Geomatrix) (Sular)Parameter n Mean SD CV % n Mean SD CV % T_(max) (hr) 96 8.59 4.07 47.3994 7.35 4.12 56.04 C_(max) (ng/mL) 96 0.858 0.844 98.42 94 0.971 0.85487.92 AUC_(last) 96 13.29 9.135 68.74 94 14.54 9.864 67.81 (hr * ng/mL)AUC_(inf) 96 13.80 9.435 68.37 94 15.28 10.43 68.25 (hr * ng/mL)AUC_(Extrap) (%) 96 3.77 3.31 87.74 94 4.46 5.69 127.74 λ_(z) (hr⁻¹) 960.0530 0.0162 30.60 94 0.0494 0.0171 34.68 T_(1/2) (hr) 96 14.46 4.8933.85 94 16.53 8.54 51.67 T_(last) (hr) 96 72.00 0.00 0.00 94 72.00 0.010.01 C_(last) (ng/mL) 96 0.0223 0.0209 93.78 94 0.0247 0.0246 99.66

TABLE 16 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of Nisoldipine Comparing Test Formulation 16-E (Geomatrix,Treatment A) to the Reference Product (Sular, Treatment B) DependentGeometric Mean^(a) Ratio (%)^(b) 90% CI^(c) Variable Test Ref (Test/Ref)Lower Upper Power ln (C_(max)) 0.7013 0.7942 88.30 81.68 95.46 0.9985 ln(AUC_(last)) 11.5097 12.5263 91.88 86.66 97.42 1.0000 ln (AUC_(inf))11.9760 13.1365 91.17 85.93 96.72 1.0000

It is understood that the disclosed methods are not limited to theparticular methodology, protocols, and reagents described as these mayvary. It is also to be understood that the terminology used herein isfor the purpose of describing particular embodiments only, and is notintended to limit the scope of the present invention which will belimited only by the appended claims.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of skill in the artto which the disclosed invention belongs.

1. A controlled release solid oral dosage formulation comprising (a) acore comprising one or more active agents and one or more entericmaterials; and optionally (b) one or more barrier layers comprising oneor more swellable, erodible, or gellable polymers, wherein, uponadministration to a subject, the active agent is released with anascending release rate in response to the changes in pH as the dosageformulation descends the GI tract.
 2. The formulation of claim 1,wherein the one or more active agents is selected from the groupconsisting of hypnotics, sedatives, tranquilizers, anti-convulsants,musclerelaxants, analgesics, anti-inflammatory, anesthetics,anti-spasmodics, anti-ulcer-agents, anti-parasitics, anti-microbials,anti-fungal, cardiovascular agents, diuretics, cytostatics,anti-neoplastic agents, anti-viral agents, anti-glaucoma agents,anti-depressants, sympathomimetics, hypoglycaemics, diagnostic agents,anti-cough, physic energizers, anti-parkinson agents, local anesthetics,muscle contractants, anti-malarials, hormonal agents, contraceptives,anorexic, anti-arthritic, anti-diabetic, anti-hypertensive,anti-pyretic, anti-cholingergic, bronchodilator, central nervous system,inotropic, vasodilator, vasoconstrictor, decongestant, hematinic,electrolyte supplement, germicidal, parasympathetolytic,parasymphatethomimetic, antiemetic, psychostimulant, vitamin,beta-blockers, H-2 blocker, beta-2 agonist, counterirritants,coagulating modifying agents, stimulants, anti-hormones,drug-antagonists, lipid-regulating agents, uricosurics, cardiacglycosides, ergot and derivatives thereof, expectorants, musclerelaxants, anti-histamines, purgatives, contrast materials,radiopharmaceuticals, imaging agents, anti-allergic agents, andcombinations thereof.
 3. The formulation of claim 1, wherein theconcentration of the one or more active agents is from about 0.1% toabout 90% by weight of the composition, from about 0.5% to about 20% byweight of the composition, or from about 1% to about 10% by weight ofthe composition.
 4. The formulation of claim 1, wherein the one or moreenteric materials is selected from the group consisting of celluloseacetate phthalate, alginates, alkali-soluble acrylic resins,hydroxypropyl methylcellulose phthalate, methacrylate-methacrylic acidco-polymers, polyvinyl acetate phthalate, styrol maleic acid copolymers,and combinations thereof.
 5. The formulation of claim 1, wherein theconcentration of the one or more enteric materials is from bout 0.1% toabout 20% by weight of the compositions, from about 1 to about 15% byweight of the composition, or from about 5 to about 10% by weight of thecomposition.
 6. The formulation of claim 1, wherein the core or centrallayer further comprises one or more non-enteric polymeric materials thatmodulate the release of the calcium channel blocker.
 7. The formulationof claim 6, wherein the one or more non-enteric polymeric materials areselected from the group consisting of crosslinked polyvinylpyrrolidone,hydroxypropylmethylcellulose, hydroxypropylcellulose, crosslinked sodiumcarboxymethylcellulose, carboxymethyl starch, acrylic and methacrylicacid polymers and copolymers, polyesters, polyanhydrides,polymethylvinylether/anhydride copolymers, potassiummethacrylate-divinylbenzene copolymer, polyvinylalcohols, glucan,scleroglucan, mannan, starch and derivatives thereof, betacyclodextrins,cyclodextrin derivatives containing linear and/or branched polymericchains, and combinations thereof.
 8. The formulation of claim 7, whereinthe one or more polymeric materials that modulate the release of thecalcium channel blocker are present in a concentration from about 1% toabout 90% by weight of the core, or from about 10% to about 45% byweight of the core.
 9. The formulation of claim 1, wherein the one ormore swellable, erodible, or gellable polymers are selected from thegroup consisting of hydroxypropylmethylcellulose, carboxyvinyl polymers;polyvinylalcohols; glucans, scleroglucans; mannans; xantans; alginatesand derivatives thereof; polyanhydrides; polyaminoacids;methylvinylether/maleic anhydride copolymers; carboxymethylcellulose andderivatives thereof; ethylcellulose, methylcellulose, and othercellulosic derivatives; and combinations thereof.
 10. The formulation ofclaim 1, wherein the concentration of the one or more swellable,erodible, and/or gellable polymers is from about 5% and to about 90% byweight of the barrier layer(s) or from about 25% and to about 75% byweight of the barrier layer(s).
 11. The formulation of claim 10, whereinthe polymer is hydroxypropylmethylcellulose.
 12. The formulation ofclaim 1, wherein the core and/or the barrier layer further comprise oneor more excipients selected from the group consisting of plasticizers,diluents, binders, lubricants, surfactants, pH modifying agents,anti-adherents, disintegrators, fillers, pigments, colorants,stabilizing agents, flavoring agents, glidants, and combinationsthereof.
 13. The formulation of claim 1, wherein the formulation is inthe form of a tablet or caplet.
 14. The formulation of claim 1, whereinthe central layer and/or the barrier layer further comprises one or moreadjuvants that further modulate the release of the active agent selectedfrom the group consisting of glyceryl monostearate, triglyceridederivatives, semi-synthetic glycerides, hydrogenated castor oil,glyceryl palmitostearate, cetyl alcohol, polyvinylpyrrolidone, glycerol,ethylcellulose, methylcellulose, sodium carboxymethylcellulose,magnesium stearate, stearic acid, talc, sodium benzoate, boric acid,polyoxyethylenglycols, colloidal silica, and combinations thereof. 15.The formulation of claim 1, further comprising one or more coatingmaterials which modulate release of the active agent.
 16. Theformulation of claim 15, wherein the one or more coating materials areselected from the group consisting of immediate release coatings, tastemasking coatings, sustained released coatings, enteric coatings, delayedrelease coatings, and combinations thereof.
 17. A method of treating acardiovascular disorder, the method comprising administering to apatient in need thereof a formulation comprising (a) a core comprisingone or more active agents and one or more enteric materials; andoptionally (b) one or more barrier layers comprising one or moreswellable, erodible, or gellable polymers, wherein, upon administrationto a subject, the active agent is released with an ascending releaserate in response to the changes in pH as the dosage formulation descendsthe GI tract.
 18. The method of claim 17, wherein the concentration ofthe one or more active agents is from about 0.1% to about 90% by weightof the composition, from about 0.5% to about 20% by weight of thecomposition, or from about 1% to about 10% by weight of the composition.19. The method of claim 17, wherein the one or more enteric materials isselected from the group consisting of cellulose acetate phthalate,alginates, alkali-soluble acrylic resins, hydroxypropyl methylcellulosephthalate, methacrylate-methacrylic acid co-polymers, polyvinyl acetatephthalate, styrol maleic acid copolymers, and combinations thereof. 20.The method of claim 17, wherein the concentration of the one or moreenteric materials is from bout 0.1% to about 20% by weight of thecompositions, from about 1 to about 15% by weight of the composition, orfrom about 5 to about 10% by weight of the composition.
 21. The methodof claim 17, wherein the core or central layer further comprises one ormore non-enteric polymeric materials that modulate the release of thecalcium channel blocker.
 22. The method of claim 17, wherein the one ormore non-enteric polymeric materials are selected from the groupconsisting of crosslinked polyvinylpyrrolidone,hydroxypropylmethylcellulose, hydroxypropylcellulose, crosslinl(edsodium carboxymethylcellulose, carboxymethyl starch, acrylic andmethacrylic acid polymers and copolymers, polyesters, polyanhydrides,polymethylvinylether/alnhydride copolymers, potassiummethacrylate-divinylbenzene copolymer, polyvinylalcohols, glucan,scleroglucaln, mannan, starch and derivatives thereof betacyclodextrins,cyclodextrin derivatives containing linear and/or branched polymericchains, and combinations thereof.
 23. The method of claim 17, whereinthe one or more polymeric materials that modulate the release of thecalcium channel blocker are present in a concentration from about 1% toabout 90% by weight of the core, or from about 10% to about 45% byweight of the core.
 24. The method of claim 17, wherein the one or moreswellable, erodible, or gellable polymers are selected from the groupconsisting of hydroxypropylmethylcellulose, carboxyvinyl polymers;polyvinylalcohols; glucans, scleroglucans; mannans; xantans; alginatesand derivatives thereof; polyanhydrides; polyaminoacids;methylvinylether/maleic anhydride copolymers; carboxymethylcellulose andderivatives thereof; ethylcellulose, methylcellulose, and othercellulosic derivatives; and combinations thereof.
 25. The method ofclaim 17, wherein the concentration of the one or more swellable,erodible, and/or gellable polymers is from about 5% and to about 90% byweight of the barrier layer(s) or from about 25% and to about 75% byweight of the barrier layer(s).